Abstract 1291: Human Apo A-I Transfer attenuates Transplant Arteriosclerosis via Enhanced Incorporation of Bone Marrow-derived Endothelial Progenitor Cells
Background and Objectives: Transplant arteriosclerosis is the leading cause of graft failure and death in patients with heart transplantation. Endothelial progenitor cells (EPCs) contribute to endothelial regeneration in allografts. Hypercholesterolemia is associated with impaired number and function of EPCs in patients with coronary artery disease and in apo E deficient mice. Here, we investigated whether increased HDL cholesterol following adenoviral human apo A-I (AdA-I) transfer increases number and function of EPCs in hypercholesterolemic apo E deficient mice. Using a paratopic model of transplant arteriosclerosis, we evaluated whether AdA-I transfer promotes incorporation of EPCs in allografts and attenuates transplant arteriosclerosis in C57BL/6 apo E deficient mice.
Methods and Results: Compared to baseline, AdA-I transfer resulted in a 3.0-fold (p<0.01) and 2.5-fold (p<0.01) increase of HDL cholesterol levels at day 14 and day 35 after transfer, respectively. EPC number in apo E deficient mice was increased after AdA-I transfer as evidenced by 1.5-fold (p<0.01) higher Flk-1 Sca-1 positive cells and 1.4-fold (p<0.01) higher DiI-acLDL isolectin positive spleen cells. In addition, HDL enhanced EPC function in migration assays. The common carotid artery of female Balb/c mice (H2d) was transplanted paratopically to male C57BL/6 apo E deficient mice (H2b) two weeks after gene transfer or saline injection. Incorporation of bone marrow-derived EPCs was 5.8-fold (p<0.01) higher at day 21 after transplantation in AdA-I treated apo E deficient mice compared to control mice. Enhanced endothelial regeneration in AdA-I treated apo E deficient mice as evidenced by a 2.6-fold (p<0.01) increase of CD31 positive endothelial cells resulted in a 1.4-fold (p<0.059) reduction of neointima and a 3.9-fold (p<0.01) increase of luminal area at day 21 after transplantation. In addition, the number of infiltrating macrophages was 1.4-fold (p<0.05) lower in the allografts of AdA-I treated mice than in control mice.
Conclusion: Human apo A-I transfer increases number and function of EPCs, enhances incorporation of EPCs into allografts, promotes endothelial regeneration and attenuates transplant arteriosclerosis in apo E deficient mice.